CN109232540A - 一种取代苯并咪唑衍生物及应用 - Google Patents
一种取代苯并咪唑衍生物及应用 Download PDFInfo
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- CN109232540A CN109232540A CN201811361547.9A CN201811361547A CN109232540A CN 109232540 A CN109232540 A CN 109232540A CN 201811361547 A CN201811361547 A CN 201811361547A CN 109232540 A CN109232540 A CN 109232540A
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- cancer
- benzimidazole derivative
- substituted benzimidazole
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- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title abstract 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 229940002612 prodrug Drugs 0.000 claims abstract description 5
- 239000000651 prodrug Substances 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 3
- -1 Cyano Chemical group 0.000 claims description 24
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- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
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- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
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- TUWZZXGAUMSUOB-UHFFFAOYSA-N benzyl piperidine-1-carboxylate Chemical compound C1CCCCN1C(=O)OCC1=CC=CC=C1 TUWZZXGAUMSUOB-UHFFFAOYSA-N 0.000 description 1
- VALPXRNQZYGXPS-UHFFFAOYSA-N benzyl pyrrolidine-1-carboxylate Chemical compound C1CCCN1C(=O)OCC1=CC=CC=C1 VALPXRNQZYGXPS-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
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Abstract
本发明属于医药化学领域，涉及一种取代苯并咪唑衍生物及应用。该取代苯并咪唑衍生物为式I所示的化合物，或其互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物，或其前体药物，或其药学上可接受的盐、溶剂合物或水合物。其可作为治疗上有效的PARP抑制剂，用于预防和治疗与PARP相关疾病。
Description
技术领域
本发明属于医药化学领域，更具体地，涉及一种取代苯并咪唑衍生物及应用。
背景技术
PARP是聚二磷酸腺苷核糖聚合酶(poly(ADP-ribose)polymerase)的简称，是一种与单链DNA损伤修复密切相关的核酶，对修复DNA的损伤并维持基因组的完整起着关键作用，也是近年来癌症治疗中的一个热门药物靶点。研究发现，PARP-1抑制剂单药对BRCA1/2突变的乳腺癌及卵巢癌细胞有明显抑制作用。若肿瘤细胞HR修复途径中的任一基因(如BRCA1/2)突变或表达沉默，即会引起HR修复途径缺陷，PARP抑制剂即可能通过合成致死作用发挥抗肿瘤活性。另外，PARP抑制剂还可作为放(化)疗增敏剂发挥抗肿瘤作用。许多化疗药物和放疗均通过直接或间接损伤DNA来发挥对肿瘤细胞的杀伤作用。由于PARP在DNA损伤修复中起关键作用，可将PARP抑制剂作为放(化)疗增敏剂与放(化)疗联用，增强抗肿瘤疗效。同时，还可因此减少放(化)疗用药或放射剂量，降低毒副作用。临床前及临床数据表明PARP抑制剂用于治疗卵巢癌、三阴性乳腺癌、胃癌、小细胞肺癌、神经胶质瘤有巨大的潜力。多个抑制剂在临床试验都在高度恶性浆液性卵巢癌和三阴性乳腺癌中有抑制肿瘤，延长无进展生存期的效果。作为化疗及放疗增敏剂，多个抑制剂与替莫唑胺或其他化疗药物联用在小细胞肺癌和神经胶质瘤中进行临床试验。
PARP抑制剂的研究从上世纪70年代就已开始，目前主要针对PARP的DNA损伤修复功能，应用于肿瘤治疗，但是直到2003年才有候选药物进入临床研究阶段。2014年AstraZeneca研发的Olaparib同时在欧盟和美国被批准上市用于晚期卵巢癌的治疗，标志着PARP作为抗肿瘤靶点和协同致死理论的可行性首次在临床确立；2016年12月ClovisOncology研制的Rucaparib在美国被批准上市以及Tesaro研制的niraparib在晚期卵巢癌III期临床试验中取得巨大成功，进一步巩固了PARP抑制剂在抗肿瘤领域的重要地位；Veliparib于2006年进入临床试验阶段，目前处于III期临床，主要用于与各种化疗药物联合用药；Talazoparib是目前为止报道活性最高的PARP抑制剂，其在酶活性水平上是其他已上市或临床在研抑制剂的3～8倍。汤森路透数据预测，至2020年，Olaparib、Rucaparib、Niraparib和Veliparib产品合计销售额将达25亿美元。
因而，开发出更安全、高效的治疗癌症的新型PARP抑制剂药物具有巨大的社会价值和经济效益，也是目前各大医药企的研究热点。寻找具有PARP抑制活性的新型化合物，改善抗肿瘤药物的耐药性和成药性，提高其生物活性和生物利用度，对于临床相关疾病治疗具有重要意义。
发明内容
本发明的目的是提供一种取代苯并咪唑衍生物，可作为治疗上有效的多聚(ADP-核糖)聚合酶(PARP)抑制剂，用于预防和治疗与PARP相关疾病。
为了实现上述目的，本发明的第一方面提供一种取代苯并咪唑衍生物，该取代苯并咪唑衍生物为式I所示的化合物，或其互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物，或其前体药物，或其药学上可接受的盐、溶剂合物或水合物，
其中，
A为饱和的或单不饱和的4-元到8-元杂环，杂环上含有一或两个氮原子以及任选的氧原子和/或硫原子；
X为直链或支链的C1-C8亚烷基，其中的碳原子任选的具有＝O基团；
Y为C6-C10芳基或C4-C10杂芳基，且任选的被1、2或3个下列基团取代：氟、氯、溴、碘、直链或支链的C1-C4烷基、硝基、CF3、氰基、C2-C8烯基、C2-C8炔基、C1-C4烷氧基或NR1aR1b，其中R1a和R1b各自独立地选自氢或C1-C4烷基。
根据本发明，优选地，A为哌啶环或吡咯环；进一步优选地，A为4-位与苯并咪唑键合的哌啶环或3-位与苯并咪唑键合的吡咯环。
根据本发明，优选地，X与A上的氮原子键合，X优选选自直链或支链的C1-C4亚烷基，X中与Y相连的C原子任选的具有＝O基团；具体优选地，X选自亚甲基、亚乙基、亚异丙基或式II所示基团；
根据本发明，Y优选选自C6-C8芳基或C4-C6杂芳基，且任选的被1个下列基团取代：C1-C4烷基、C1-C4烷氧基或氨基；具体优选地，Y选自苯基、甲苯基、氨基苯基、甲氧基苯基、吡啶基、呋喃基、吡咯基、吲哚基。
式I所示化合物可以为外消旋物、对映异构纯的化合物或非对映异构体的形态。如果要求对映异构纯的化合物，例如可以通过用式I所示化合物或它们的用在合适的旋光活性碱或酸中的中间体进行外消旋物的经典拆分而获得。
饱和或单不饱和的环状结构A可以是顺式异构体、反式异构体或其混合物。
本发明还涉及式I所示化合物的药学上可接受的盐，包括无机盐和有机盐，例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、甲磺酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、扁桃体酸盐、乳酸盐和草酸盐。可以通过式I所示化合物与合适的酸的反应而得到上述盐。
本发明中，所述前体药物被理解为意味着那些通过体内代谢可得到式I所示化合物的化合物。典型的前体药物是式I所示化合物的磷酸酯、与氨基酸形成的氨基甲酸酯、以及其它酯。
本发明的典型化合物包括但不限于以下化合物中的至少一种：
本发明所述取代苯并咪唑衍生物通过以下反应步骤合成得到。
步骤1：式III所示的1-Cbz保护的环烷甲酸(其中A为饱和的或单不饱和的4-元到8-元杂环，优选饱和的5-元或6-元杂环)与式IV所示化合物、CDI、吡啶接触反应，溶剂可为DMF，在40-60℃下加热1-3h，加入式IV所示化合物，室温反应过夜。减压浓缩，纯化后得到式V所示化合物。
步骤2：式V所示化合物混悬于乙酸中加热回流，反应产物浓缩、中和、洗涤、干燥后，得到式VI所示化合物。
步骤3：式VI所示化合物在氢气气氛下，用Pd/C催化反应，滤除固体后，浓缩滤液，得到式VII所示化合物。
步骤4：式VII所示化合物与相应的醛类、酮类(式VIII所示化合物，其中，X1为直链或支链的C1-C8亚烷基，Y为C6-C10芳基或C4-C10杂芳基，且任选的被1、2或3个下列基团取代：氟、氯、溴、碘、直链或支链的C1-C4烷基、硝基、CF3、氰基、C2-C8烯基、C2-C8炔基、C1-C4烷氧基或NR1aR1b，其中R1a和R1b各自独立地选自氢或C1-C4烷基)接触，在氰基硼氢化钠存在下进行反应，得到式IX所示化合物。
基于上述反应过程，其他取代苯并咪唑衍生物可通过选择相应的式III所示化合物获得。具体物质、反应条件均可通过本领域技术常规技术手段确定。
本发明的第二方面提供上述取代苯并咪唑衍生物在制备预防和/或治疗与PARP酶相关疾病的药物中的应用。
其中，其中，所述与PARP酶相关疾病包括但不限于癌症、缺血性疾病和神经退行性疾病。所述癌症可选自乳腺癌、卵巢癌、前列腺癌、结直肠癌、胰腺癌、肝癌、黑色素瘤、胃癌或其他实体瘤；所述神经退行性疾病可包括帕金森氏症、阿尔兹海默症。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式，然而应该理解，可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
实施例1
2-(1-(吡啶-2-甲基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
实施例1A
3-((2-氨基-3-氨基甲酰基苯基)氨基甲酰基)吡咯烷-1-甲酸苄酯
1-Cbz-3-吡咯烷甲酸(10.6g,42.71mmol)在吡啶(40mL)和DMF(40mL)的混合溶液加热至45℃，加入CDI(7.6g,46.59mmol)反应2小时后，加入式IV所示化合物(8.7g,38.82mmol)，在室温下过夜反应。减压浓缩后，加入乙酸乙酯和饱和碳酸氢钠搅拌1h。过滤收集固体物质，用水洗，干燥后得到10.5g P1A，收率70.7％。
实施例1B
3-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)吡咯烷-1-甲酸苄酯
将P1A(10.5g,27.46mmol)混悬于乙酸(100mL)中，加热回流3小时。冷却后，将溶液浓缩，残留物质用乙酸乙酯稀释，用饱和碳酸氢钠溶液调节至弱碱性。有机相用饱和食盐水洗，用无水Na2SO4干燥后浓缩。残留物用乙酸异丙酯重结晶，得到9.23g P1B，收率92.3％。
实施例1C
2-(吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
P1B(9.23g,25.33mmol)的甲醇(250mL)溶液在50psi的氢气氛围下用10％Pd/C(540mg)50℃催化反应4小时。滤除固体物质，将滤液浓缩。向残渣物中加入石油醚，该溶液在室温下搅拌过夜。将溶液过滤，滤饼收集干燥后得到5.80g P1C，收率99.4％。MS(ESI,pos,ion):231.1[M+H]+；1H NMR(400MHz,D2O)δ7.52–7.30(m,2H),7.13–6.94(m,1H),3.77–3.33(m,2.5H),3.24–3.01(m,2.5H),2.39–2.21(m,1H),2.11–1.96(m,1H).
实施例1D
2-(1-(吡啶-2-甲基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺(化合物1)
P1C(300mg,1.30mmol)，吡啶-2-甲醛(167.46mg,1.56mmol)和氰基硼氢化钠(163.74mg,2.61mmol)加入到甲醇(12mL)中。该溶液在室温下搅拌反应7小时，将溶液溶缩。残留物用柱层析法(硅胶，二氯甲烷/甲醇)纯化，得到96mg化合物1，收率22.9％。1H NMR(400MHz,DMSO)δ9.10(s br,1H),8.51(d,J＝4.2Hz,1H),7.90–7.74(m,2H),7.75–7.56(m,2H),7.46(d,J＝7.8Hz,1H),7.34–7.15(m,2H),3.97(s,2H),3.75–3.72(m,1H),3.29–3.14(m,1H),3.13–3.01(m,1H),2.99–2.79(m,2H),2.44–2.27(m,1H),2.29–2.09(m,1H).
实施例2
2-(1-((1H-吲哚-5-基)甲基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
化合物2的合成参照实施例1方法进行，用吲哚-5-甲醛代替吡啶-2-甲醛，将实施例1D的反应温度改为在50℃。1H NMR(400MHz,MeOD)δ7.91(d,J＝7.0Hz,1H),7.77(d,J＝1.1Hz,1H),7.72(dd,J＝8.0,0.7Hz,1H),7.52(d,J＝8.4Hz,1H),7.40–7.31(m,2H),7.29(dd,J＝8.4,1.7Hz,1H),6.55(dd,J＝3.1,0.7Hz,1H),4.56–4.44(m,2H),4.07(dt,J＝15.5,7.6Hz,1H),3.93–3.75(m,2H),3.64–3.45(m,2H),2.75–2.61(m,1H),2.50(dt,J＝20.8,7.1Hz,1H).
实施例3
2-(1-(3-氧-3-苯丙基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
将P1C(300mg,1.30mmol)，3-氯代苯丙酮(263.62mg,1.56mmol)和碳酸钾(360.11mg,2.61mmol)加入到DMF(12mL)中，在50℃下搅拌3小时，将溶液浓缩。残留物用柱层析法(硅胶，二氯甲烷/甲醇)纯化，得到化合物3(326mg，收率69.0％)。1H NMR(400MHz,DMSO)δ9.10(s,1H),8.05–7.94(m,2H),7.80(d,J＝7.5Hz,1H),7.77–7.60(m,3H),7.60–7.48(m,2H),7.34–7.19(m,1H),4.08–3.96(m,1H),3.93–3.79(m,1H),3.72–3.60(m,3H),3.60–3.43(m,4H),2.62–2.49(m,1H),2.35(s,1H).
实施例4
2-(1-(1-(4-甲氧基苯基)丙-2-基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
化合物4的合成参照实施例1方法进行，用对甲氧基苯基丙酮代替吡啶-2-甲醛，将实施例1D的反应温度改为在50℃。1H NMR(400MHz,MeOD)δ7.91(d,J＝7.5Hz,1H),7.73(d,J＝7.9Hz,1H),7.41–7.32(m,1H),7.20(d,J＝8.3Hz,2H),6.92(d,J＝7.1Hz,2H),4.00–3.89(m,1H),3.86–3.75(m,4H),3.74–3.55(m,2H),3.44–3.36(m,2H),3.31–3.18(m,2H),2.68–2.54(m,2H),2.48–2.36(m,1H),1.21(s,3H).
实施例5
2-(1-(4-(二甲氨基)苄基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
化合物5的合成参照实施例1方法进行，用对二甲胺基苯甲醛代替吡啶-2-甲醛，将实施例1D的反应温度改为在50℃。1H NMR(400MHz,DMSO)δ9.03(s,1H),7.79(d,J＝7.5Hz,1H),7.71(s,1H),7.66(d,J＝7.9Hz,1H),7.31–7.16(m,3H),6.69(d,J＝8.6Hz,2H),4.06–3.86(m,2H),3.87–3.74(m,1H),3.45–3.28(m,1H),3.28–3.13(m,1H),3.13–2.95(m,2H),2.86(s,6H),2.46–2.33(m,1H),2.34–2.20(m,1H).
实施例6
2-(1-((1H-吡咯-2-基)甲基)吡咯烷-3-基)-1氢-苯并[d]咪唑-4-甲酰胺
化合物6的合成参照实施例1方法进行，用1H-吡咯-2-甲醛代替吡啶-2-甲醛，将实施例1D的反应温度改为在50℃。1H NMR(400MHz,MeOD)δ7.91(dd,J＝7.6,0.8Hz,1H),7.73(dd,J＝8.0,0.8Hz,1H),7.36(t,J＝7.8Hz,1H),6.92(dd,J＝2.7,1.5Hz,1H),6.42(dd,J＝3.4,1.3Hz,1H),6.27–6.14(m,1H),4.48(s,2H),4.06(ddd,J＝15.2,8.4,6.7Hz,1H),3.99–3.89(m,1H),3.89–3.76(m,1H),3.66–3.43(m,2H),2.79–2.58(m,1H),2.55–2.37(m,1H).
实施例7
2-(1-(1H-吲哚-5-基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-4-甲酰胺
实施例7A
4-((2-氨基-3-氨基甲酰基苯基)氨基甲酰基)哌啶-1-甲酸苄酯
N-Cbz-哌啶-4-羧酸(19.4g,73.63mmol)在吡啶(70mL)和DMF(70mL)的混合溶液加热至45℃，加入CDI(13.0g,80.33mmol)反应2小时后，加入式IV所示化合物(15.0g,66.94mmol)，移至室温下搅拌过夜。减压浓缩后，将残渣物分散于在乙酸乙酯和饱和碳酸氢钠溶液中搅拌1h，过滤收集固体物质，用水洗，干燥后得到26g P7A，收率98.0％。
实施例7B
4-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)哌啶-1-甲酸苄酯
将P7A(26g,65.58mmol)混悬于乙酸(250mL)中，加热回流3小时。冷却后，将溶液浓缩，残留物质用乙酸乙酯稀释，用饱和碳酸氢钠溶液调节至弱碱性。有机相用饱和食盐水洗，用无水Na2SO4干燥后浓缩。残留物用乙腈重结晶，得到17.9g P7B，收率72.0％。
实施例7C
2-(4-哌啶基)-1H-苯并[d]咪唑-4-甲酰胺
P7B(17.9g,47.30mmol)的甲醇(350mL)溶液在50℃的氢气氛围下用10％Pd/C(1.8g)50℃催化反应4小时。滤除固体物质，将滤液浓缩干燥后得到11.5g P7C，收率99.5％。
实施例7D
2-(1-(1H-吲哚-5-基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-4-甲酰胺
将P7C(250mg,1.02mmol)，吲哚-5-甲醛(132mg,1.23mmol)和氰基硼氢化钠(129mg,2.05mmol)加入到甲醇(10mL)中，在50℃下搅拌反应过夜，将溶液浓缩。残留物用柱层析法(硅胶，二氯甲烷/甲醇)纯化，得到标题产物78mg，收率22.7％。1H NMR(400MHz,DMSO)δ12.81(s,1H),11.29(s,1H),9.26(s,1H),7.86–7.60(m,4H),7.48(d,J＝8.3Hz,1H),7.45–7.39(m,1H),7.28(t,J＝7.7Hz,1H),7.21(d,J＝8.3Hz,1H),6.49(s,1H),4.36(s,2H),3.57–3.35(m,4H),3.29–3.20(m,1H),2.39–2.18(m,2H),2.18–1.89(m,2H).
实施例8
2-(1-(1-(4-甲氧基苯基)丙-2-基)哌啶-4-基)-1H-苯并[d]咪唑-4-甲酰胺
化合物8的合成按实施例7方法进行，用对甲氧基苯基丙酮代替吲哚-5-甲醛。1HNMR(400MHz,DMSO)δ12.70(s,1H),9.36(s,1H),7.81(d,J＝7.6Hz,1H),7.70(d,J＝2.9Hz,1H),7.63(d,J＝7.9Hz,1H),7.27(t,J＝7.8Hz,1H),7.11(d,J＝8.5Hz,2H),6.84(d,J＝8.6Hz,2H),3.71(s,3H),3.08–2.75(m,5H),2.59–2.51(m,1H),2.40(dd,J＝13.9,10.6Hz,2H),2.20–1.95(m,2H),1.95–1.72(m,2H),0.90(d,J＝6.3Hz,3H).
实施例9
2-(1-(3-氧-3-苯丙基)哌啶-4-基)-1氢-苯并[d]咪唑-4-甲酰胺
将P7C(300mg,1.30mmol)，3-氯代苯丙酮(263.62mg,1.56mmol)和碳酸钾(360.11mg,2.61mmol)加入到DMF(12mL)中，在50℃下搅拌3小时，将溶液浓缩。残留物用柱层析法(硅胶，二氯甲烷/甲醇)纯化，得到化合物10。1H NMR(400MHz,DMSO)δ13.01(s,1H),9.30(d,J＝2.4Hz,1H),8.00(d,J＝7.4Hz,2H),7.80(d,J＝7.5Hz,1H),7.74(d,J＝2.7Hz,1H),7.69–7.61(m,2H),7.57–7.50(m,2H),7.31–7.19(m,1H),3.60–3.47(m,4H),3.23–3.08(m,3H),2.95–2.75(m,2H),2.30–2.18(m,2H),2.16–2.03(m,2H).
测试例1
化合物的活性检测
PARP-1酶活性的测试采用BPS Bioscience公司的化学发光试剂盒(PARP1Chemiluminescent Assay Kit，Catalog#80569)，实验程序根据分析试剂盒提供的说明书进行。
PARP-2酶活性的测试采用BPS Bioscience公司的化学发光试剂盒(PARP2Chemiluminescent Assay Kit，Catalog#80552)，实验程序根据分析试剂盒提供的说明书进行。
浓度为10nM的化合物对PARP-1和PARP2酶活性的抑制率，以及部分化合物对PARP-1和PARP2酶活性的抑制效应的IC50值总结在下表2中。
表2
以上已经描述了本发明的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。
Claims (10)
1.一种取代苯并咪唑衍生物，其特征在于，该取代苯并咪唑衍生物为式I所示的化合物，或其互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物，或其前体药物，或其药学上可接受的盐、溶剂合物或水合物，
其中，
A为饱和的或单不饱和的4-元到8-元杂环，杂环上含有一或两个氮原子以及任选的氧原子和/或硫原子；
X为直链或支链的C1-C8亚烷基，其中的碳原子任选的具有＝O基团；
Y为C6-C10芳基或C4-C10杂芳基，且任选的被1、2或3个下列基团取代：氟、氯、溴、碘、直链或支链的C1-C4烷基、硝基、CF3、氰基、C2-C8烯基、C2-C8炔基、C1-C4烷氧基或NR1aR1b，其中R1a和R1b各自独立地选自氢或C1-C4烷基。
2.根据权利要求1所述的取代苯并咪唑衍生物，其中，A为哌啶环或吡咯环；优选地，A为4-位与苯并咪唑键合的哌啶环或3-位与苯并咪唑键合的吡咯环。
3.根据权利要求1所述的取代苯并咪唑衍生物，其中，X与A上的氮原子键合。
4.根据权利要求1所述的取代苯并咪唑衍生物，其中，X选自直链或支链的C1-C4亚烷基，X中与Y相连的C原子任选的具有＝O基团。
5.根据权利要求4所述的取代苯并咪唑衍生物，其中，X选自亚甲基、亚乙基、亚异丙基或式II所示基团；
6.根据权利要求1所述的取代苯并咪唑衍生物，其中，Y选自C6-C8芳基或C4-C6杂芳基，且任选的被1个下列基团取代：C1-C4烷基、C1-C4烷氧基或氨基；优选选自苯基、甲苯基、氨基苯基、甲氧基苯基、吡啶基、呋喃基、吡咯基或吲哚基。
7.根据权利要求1所述的取代苯并咪唑衍生物，其中，所述式I所示化合物选自以下化合物中的至少一种；
8.权利要求1-7中任意一项所述的取代苯并咪唑衍生物在制备预防和/或治疗与PARP酶相关疾病的药物中的应用。
9.根据权利要求8所述的应用，其中，所述与PARP酶相关疾病包括癌症、缺血性疾病和神经退行性疾病。
10.根据权利要求8所述的应用，其中，所述癌症选自乳腺癌、卵巢癌、前列腺癌、结直肠癌、胰腺癌、肝癌、黑色素瘤、胃癌或其他实体瘤；所述神经退行性疾病包括帕金森氏症、阿尔兹海默症。
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